Medical consequences of alcohol abuse.

Studies have shown that long-term alcohol abuse produces serious, harmful effects on a variety of the body's organ systems. Parts of the human body most affected include the liver and the immune, cardiovascular, and skeletal systems. Current research has examined some of these effects in an effort to better understand the medical consequences of alcohol use and abuse and to ultimately develop more effective treatments for responding to alcohol-induced bodily damage. This article discusses some of those findings.

L ong-term alcohol abuse is known to e xe rt harmful effects on a number of the body's organ systems. Those most affected by alcohol abuse include the liver and the immune, card i ova s c ul a r, and skeletal systems. Many of the mechanisms invo l ved in alcohol's effects on these systems are not yet completely understood. Consequently, recent re s e a rc h has examined some of alcohol's medical consequences in an effort to incre a s e understanding and develop appro p r i a t e and effective tre a t m e n t s .

Alcoholic Liver Disease
The liver is a vital organ invo l ved in p rocessing fats, sugars, proteins, and vitamins and in regulating blood clotting. It plays a central role in the body's defenses, filtering toxins and micro b e s f rom the blood and marshaling an array of responses to trauma, stress, or inflammation.
Although the liver is capable of re g e ne r a t i o n and re p a i r, seve re liver disease can be life threatening. Long-term, heavy alcohol use is the leading cause of illness and death from liver disease in the United States. The number of persons with alcoholic liver disease (ALD), which ranges in severity fro m fatty liver to end-stage cirrhosis, is con-s e rva t i vely estimated at more than 2 million. Women, compared with men, d e velop alcoholic hepatitis and alcoholic cirrhosis after fewer years of drinking and from ingesting smaller daily amounts of alcohol. Rat studies confirm gre a t e r l i ver damage in females than in males at the same blood alcohol concentration ( B AC ) .
T h e re are three forms of ALD: fatty l i ve r, which is usually re versible with abstinence; alcoholic hepatitis, charact e r i zed by persistent liver inflammation; and cirrhosis, characterized by pro g re ss i ve scarring of liver tissue. A person can h a ve more than one type of liver disease. Patients with both cirrhosis and alcoholic hepatitis have a death rate of more than 60 percent over a 4-year period, with most deaths occurring within the first 12 months of diagnosis.
The major problem in deve l o p i n g n ew therapies for ALD has been a lack of understanding of the mechanisms for l i ver injury. Howe ve r, much has been learned recently as a result of better technology and advances in re s e a rc h .

The Process of Inflammation
Long-term alcohol consumption has been shown to prolong the natural i n f l a m m a t o ry responses of the live r. Inflammation functions to pre vent the s p read of localized injury or infection while mobilizing the defense mechanisms of the immune system. An important aspect of liver inflammation is the p roduction of chemical messengers called cytokines, which help regulate the inflamm a t o ry p rocess. Cytokines attract and a c t i vate cells of the immune system, promote scar formation, and stimulate the p roduction of additional chemical messeng e r s , including more cytokines. Howe ve r, if the increased levels of cytokines do not subsequently return to normal, they can cause chronic inflammation, leading to cell injury or cell death.
Cytokine production can be stimulated by endotoxin, a substance derive d f rom the cell walls of certain bacteria that reside in the human intestine. He a v y alcohol consumption can increase the passage of endotoxin through the intestinal wall into the bloodstream. Sp e c i a l i ze d immune system cells (i.e., Kupffer cells) in the liver respond to blood-borne e n d o t oxin by producing inflammatory cytokines. These cytokines furt h e r i n c rease gut permeability, perpetuating a destru c t i ve cyc l e .
Another stimulus for exc e s s i ve cytokine production is the generation of re a c t i ve oxygen species (ROS), tox i c by -p roducts of alcohol metabolism in the live r. No r m a l l y, ROS are quickly i n a c t i vated by antioxidants, pro t e c t i ve Persistent liver inflammation is characteristic of alcoholic hepatitis and usually precedes alcoholic cirrhosis. The hallmark of cirrhosis is cytokineinduced scarring that distorts the live r's internal stru c t u re and impairs its function. Imbalances in cytokine interactions impair the normal regeneration of tissue that typically follows liver injury.

Preventing Alcoholic Liver Injury
Re s e a rchers have devised several strategies to pre vent or minimize alcoholic l i ver damage. In experiments using rats, alcohol-induced liver injury has been lessened by suppressing endotox i np roducing intestinal bacteria (e.g., t h rough the use of antibiotics); administering substances that selective l y d e s t roy Kupffer cells or that inhibit the generation of ROS; and feeding antibodies that neutralize specific cytokines.
Experiments with a soybean extract, p o l yenylphosphatidylcholine (PPC), s h owed that it could pre vent fibro s i s and cirrhosis in alcohol-fed baboons. It also reduces the formation of scar tissue and may possess antioxidant pro p e rt i e s as well. A study conducted by the U.S. De p a rtment of Veterans Affairs is currently evaluating the effects of PPC in humans with early ALD. Therapy with S-adenosyl-l-methionine (SAM) may lessen the depletion of the antiox i d a n t glutathione in liver cells. Choline and methionine, dietary factors related to SAM, may help protect against endot oxin-induced liver injury in rats.

Alcohol's Effects on the Immune System
For 200 years physicians have observe d that exc e s s i ve alcohol consumption can lead to increased illness and death fro m infectious diseases. Alcohol abusers suffer f rom increased susceptibility to bacterial pneumonia, pulmonary tuberculosis, and hepatitis C (HCV). Patients with ALD a re at high risk of having HCV, the leading cause of liver transplantation in the United States (National Institute on Alcohol Abuse and Alcoholism [NIAAA] 1998). Findings indicate that patients with ALD who are HCV positive have m o re seve re liver disease and are yo u n g e r than HCV-n e g a t i ve patients (NIAAA 1998). This increase in disease may re f l e c t i m p a i red immune function (i.e., immunodeficiency) caused by alcohol abuse.
Alcohol abusers may be at incre a s e d risk compared with nonabusers for infection with human immunodeficiency viru s ( H I V) from risky sex practices while i n t oxicated. Re s e a rchers also are inve s t igating whether alcohol consumption itself may increase susceptibility to HIV infection or hasten the pro g ression fro m HIV infection to full-blown AIDS.
In addition, some alcohol-re l a t e d organ damage, as in ALD, may re s u l t in part from immune system ove r a c t i v i t y in which the immune system attacks the b o d y's own tissues (i.e., autoimmunity).
Cu r rent re s e a rch is examining the effects of heavy drinking on the immune system.

How the Immune System Works
The body's first line of defense against disease is inflammation, as described e a r l i e r. Inflammation is a nonspecific response, directed against all sources of damage. When nonspecific defenses are b reached, an array of specific immune responses (see table) come into play. Specific immune responses may be b roadly classified as either cell-mediated or humoral. Cell-mediated immunity i n vo l ves direct contact between immune system cells and target cells (e.g., bacteria). Humoral immunity is provided by antibodies that circulate in the blood and lymph. Antibodies are specialize d p roteins designed to re c o g n i ze and disable specific microoganisms or tox i c substances. Antibodies that persist in the bloodstream may confer long-term immunity to a given disease.

Immune Response Function
Humoral Antibody A specialized protein that recognizes and disables specific microorganisms or toxic substances. When persisting in the bloodstream, it may help confer long-term immunity against a specific disease.

Cell-Mediated
Phagocyte A specialized cell that engulfs invading microorganisms and cell debris through a process known as phagocytosis.

Macrophage
A type of phagocyte that is the first to be activated during p h a g ocytosis. It resides in tissues and organs throughout the body.

Neutrophil
A type of phagocyte that aids in the destruction of invading microorganisms, in part by releasing toxic compounds known as reactive oxygen species (ROS). Together with monocytes, neutrophils are commonly referred to as white blood cells.
Monocyte A type of cell that is responsible for determining the "foreignness" of an invading agent and then presenting such agents to other cells for destruction. Monocytes release ROS to aid in the destruction process. They are also referred to as white blood cells.
Phagocytes are specialized cells that engulf invading microorganisms and cell debris through a process called phagoc y t o s i s . The first phagocytes to be activated are macrophages, which reside in tissues and organs throughout the body. White blood cells infiltrate the are a , with neutrophils (a type of phagocyte) being the first to arrive, followed by monocytes. Monocytes are one of the types of cells that initially determine t h e "f o re i g n n e s s" of an invading agent a n d p resent it to other cells, which re s p o n d by p roducing appropriate cytokines. Various immune cells release chemical messengers to attract more cells, and within neutrophils and macrophages, the t oxic oxygen-containing compounds ROS destroy phagocytosed micro o r g a nisms. Excess ROS, howe ve r, can damage l i ver cells.
T h roughout the immune re s p o n s e , cytokines continue their re g u l a t o ry functions. They include tumor necro s i s factor (TNF) and a family of both i n f l a m m a t o ry and anti-inflammatory substances called interleukins.

How Alcohol Affects the Immune System
Both chronic and acute alcohol administration can produce the loss of va r i o u s types of immune responses in experiment a l animals. Administration of alcohol concentrations similar to those seen in binge drinkers impairs the function of c u l t u red human monocytes and can temporarily reduce the numbers and activity of immune cells in mice. Alcohol inhibits neutrophil migration in humans and in experimental animals. Howe ve r, an infiltration of neutrophils into the l i ver is observed in alcoholic hepatitis. Experiments with alcohol-fed rats showe d that their neutrophils engulfed bacteria efficiently but did not kill all strains of pneumonia-causing bacteria with normal effective n e s s .
Although inflammatory cytokine leve l s i n c rease in ALD, endotox i n -i n d u c e d s e c retion of inflammatory cytokines in the lung may decrease in alcohol-fed animals as well as in human a l c o h o l i c s , potentially increasing susceptibility t o pneumonia. Acute administration of alcohol to rats reduced ROS pro d u c-tion by isolated lung macrophages after challenge with TB organisms.

Therapeutic Measures
Some proposed therapies include administration of such substances as antibodies against endotoxin or against specific cytokines, substances that would absorb e xcess cytokines or inhibit their function, and drugs that have a widespre a d effect (e.g., decreasing the permeability of the intestinal wall to the passage of e n d o t oxin). Administration of grow t h hormone and related chemical messengers has been shown to improve some, but not all, measures of immune function in rats.

Alcohol's Effects on the Cardiovascular System
C h ronic heavy drinking is a leading cause of card i ovascular illnesses such as d e g e n e r a t i ve disease of heart muscle ( c a rd i o m yopathy); disorders associated with decreased blood supply to the heart muscle (coro n a ry heart disease [CHD]); high blood pre s s u re; heart rhythm disorders (arrhythmias); and stro k e .

Alcoholic Cardiomyopathy
Long-term heavy drinking can cause the heart to become enlarged and lose some of its ability to contract, a condition known as alcoholic card i o m yo p at h y. These symptoms include short n e s s of breath and an insufficient blood flow to the rest of the body. Women may h a ve a greater risk than men of deve loping alcoholic card i o m yo p a t h y. The condition may be at least part i a l l y re versible with abstinence.
A l c o h o l's toxic effects on heart muscle may be mediated by increased RO S l e vels and decreased antioxidant enzyme a c t i v i t y. Another recent study found that alcohol may decrease the sensitivity of heart muscle to chemical messengers from nerve cells that regulate heart muscle metabolism and contraction.

Coronary Heart Disease
The blood that nourishes the heart musc l e is delive red through the coro n a ry a rteries. Manifestations of CHD range f rom episodic chest pain to sudden death. He a rt attacks, the most common serious manifestation of CHD, a re usually triggered by the formation of a blood clot within a coro n a ry art e ry a l ready narrowed by deposits of cholest e rol and other fatty substances. The resulting ischemia reduces the heart's pumping ability, often leading to permanent disability or death.
With few exceptions, worldwide epidemiologic data demonstrate a 20to 40-percent lower CHD incidence among drinkers compared with nondrinkers. Heavy drinkers have an i n c reased risk of death from heart disease. Howe ve r, moderate drinkers exhibit l ower rates of CHD-related mort a l i t y than both heavy drinkers and abstainers. This is confirmed by studies in which p a rticipants we re interv i ewed about their drinking habits and life styles before the onset of disease. Such studiesre p resenting a total population of more than 1 million men and women of diff e rent ethnicities followed for up to 24 years-confirm an association betwe e n moderate drinking and lower CHD risk. Howe ve r, this association does not necessarily mean that alcohol itself is the cause of the lower risk.
In addition, different epidemiologic studies apply the term "m o d e r a t e d r i n k i n g" to a wide range of consumption levels, sometimes more than the amount defined by the Di e t a ry Gu i d e l i n e s for Americans as moderate: two or f ewer standard drinks per day for men and one or less per day for women. In any case, the apparent benefits of moderate drinking on CHD mortality are offset at higher drinking levels thro u g h i n c reasing risk of death from other a l c o h o l -related causes.
Re s e a rch has suggested several possible mechanisms by which alcohol may p rotect against CHD. For example, alcohol inhibits the deposition of fatty substances within the coro n a ry art e r i e s of mice and also may inhibit the formation of blood clots within alre a d y n a r rowed coro n a ry art e r i e s .

Alcohol Research & Health
Epidemiologic data and results of studies on isolated animal hearts suggest that moderate alcohol consumption also may lower CHD mortality by i m p roving surv i val after a heart attack. Fu rther studies are needed to confirm this effect and to determine its applicability in humans.

Alcohol and Blood Pressure
An association between heavy alcohol consumption and increased blood pre ss u re has been observed in more than 60 studies in diverse cultures and populations. The effects of moderate alcohol cons u m p t i o n on blood pre s s u re are unclear.

Arrhythmias
The heart's ability to function effective l y depends on re g u l a r, synchronous contraction of the heart muscle. He a v y drinking can disrupt the heart rhythm both acutely (during an episode of drinking) and chronically (due to longterm use). In t oxication can cause cert a i n types of arrhythmia in both alcoholics and otherwise healthy persons. The d e velopment of arrhythmias with binge drinking-a condition seen most frequently around the holidays-is know n as "holiday heart syndro m e . " Sudden death attributable to arrhythm i a is one of the causes of mortality in alcoholics with or without pre -e x i s t i n g h e a rt disease. Such deaths often occur during periods of abstinence (Clark 1988), suggesting the development of arrhythmias during alcohol withdrawal.

Alcohol and Stroke
The relationship between alcohol consumption and stroke is similar to that seen with CHD. Moderate alcohol consumption appears to be associated with lower incidence of ischemic stro k e s , w h e reas heavy drinking may increase the risk of both ischemic and hemorrhagic s t rokes (i.e., bleeding within the brain).

Alcohol and Bone
Epidemiologic studies have found a significant association between alcohol consumption and risk for bone fracture . In addition to increased risk of accident a l i n j u ry through alcohol-induced impairment of gait and balance, alcoholics also may suffer from a generalize d d e c rease in bone mass, making their bones more fragile. Heavy drinking may lead to osteoporosis, characterized by s e ve re back pain, spinal deformity, and i n c reased risk of wrist and hip fracture s , although some recent studies suggest that moderate alcohol consumption may protect against osteoporo s i s .

Alcohol and Skeletal Development
Bone growth and remodeling during childhood and adolescence invo l ves the c o o rdinated activity of two types of cells: (1) osteoclasts, which break dow n (i.e., resorb) bone, and (2) osteoblasts, which form new bone.
Cyclic bone remodeling continues t h roughout adulthood to regulate and maintain bone mass. Adult bone formation and resorption rates are tightly coupled, with approximately 10 perc e n t of bone undergoing the process at any g i ven time. Be t ween ages 20 and 40, a p e r s o n's bone density begins to decline, resulting in a cumulative decrease in skeletal mass of up to 40 percent by age 70. Women experience accelerated decline in bone density following menopause and are more susceptible than men to o s t e o p o ro s i s .
Alcohol disrupts bone re m o d e l i n g in animals and humans. Overall, studies in alcoholics suggest that alcoholic bone disease invo l ves considerable suppre ssion of bone formation with essentially normal rates of resorption. The changes in bone turnover induced by alcohol can apparently be re versed by abstinence. The skeletal consequences of alcohol intake may be especially harmful during adolescence, when the rapid skeletal g rowth ultimately responsible for achievi n g peak bone mass occurs. By limiting peak bone mass attainment, the risk of d e veloping osteoporosis later in life may increase and its onset hastened.

Potential Mechanisms of Alcohol-Induced Bone Disease
Long-term consumption of alcohol disrupts the processes of bone growth and bone tissue re p a i r. A decrease in bone d e n s i t y, as well as an increased risk of bone fracture, may result. These effects of alcohol on bone may occur dire c t l y, with alcohol itself interfering with bone metabolism, or indire c t l y, with alcohol e xe rting its effects through a third part y, such as hormones. The female re p rod u c t i ve hormone estrogen appears to affect bone metabolism, although its role with respect to alcohol consumption is uncert a i n .
A number of re s e a rchers have noted that alcohol can reduce osteoblast formation. Alcohol can inhibit osteoblast p roliferation in culture at concentrations well within the drinking level observe d in alcoholics. A concentration of alcohol equivalent to a blood alcohol leve l of 0.044 percent, about half the blood alcohol level that many States define as legally intoxicated, also resulted in a 2 0 -p e rcent decline. Alcohol also may d e p ress osteoblast function by inhibiting the cell's response to insulin-like g rowth factors, chemical messengers that help regulate bone re m o d e l i n g .
Studies of alcohol's effects on osteoclast numbers have provided conflicting results. Howe ve r, alcohol incre a s e s l e vels of a specific interleukin (IL-6), which may contribute to the deve l o pment of osteoporosis by stimulating osteoclastic activity.

Breast Cancer
The lifetime risk for breast cancer among U.S. women is estimated to be as high as one in eight. Results of approx imately 50 epidemiologic studies and In t oxication can cause cert a i n types of arrhythmia in both alcoholics and otherwise healthy persons.
analyses conducted since the 1970s point to an increase in breast cancer risk associated with alcohol consumption. Controversy remains over the i n t e r p retation of these studies, howe ve r. For epidemiologists, the actual numerical association between alcohol and b reast cancer risk is considered re l at i vely modest. In addition, some studies found no link between high alcohol intake and breast cancer risk.

Mechanisms of Alcohol-Related Breast Cancer
Scientists have identified plausible biological mechanisms for alcohol's actions.
Re s e a rch findings suggest a role for alcohol in breast cancer risk in both p remenopausal and postmenopausal women. Cu m u l a t i ve lifetime exposure to estrogen is considered an import a n t contributor to breast cancer risk. A num-b e r of studies have examined whether alcohol raises estrogen levels in premenopausal and postmenopausal women. Although some studies re p o rt such an effect, the evidence is not conclusive . Alcohol may be capable of enhancing the pro g ression as well as the initiation of cancer. In c reased metastasis ( p roliferation beyond the site of origin) of implanted breast cancer cells was o b s e rved in rats given alcohol in a liquid diet. In addition, alcohol and its highly re a c t i ve metabolite acetaldehyd e also have been linked to the body's inability to repair damage to the cell's genetic material (i.e., DNA) induced by cancer-causing agents. If unre p a i re d , damage to critical regions of DNA in b reast cells could lead to mutations and the subsequent initiation of cancer. When rodents are fed alcohol, their l e vels of circulating prolactin-a hormone that can stimulate the growth of b reast tissue-increase. In addition, ROS can contribute to tumor pro m otion. Alcohol intake also decreases the immune system's ability to detect and d e s t roy cancer cells (Yirmiya and Taylor 1993). s